The present invention relates to nitrile derivatives and to pharmaceutical compositions comprising nitrile derivatives. The invention also relates to the pharmaceutically acceptable salts of such compounds, processes for the preparation of such compounds, intermediates used in the preparation of such compounds, and the uses of such compounds in treating hyperproliferative diseases, inflammatory diseases and viral and bacterial infections.
The aforementioned derivatives and their pharmaceutically acceptable salts have one or more of the following properties: AKT inhibition, inhibition of cell cycle hyperproliferation, cell cycle specific induction of apoptosis in cancer cells, inhibition of LTB4 activities, and antiangiogenic activities showing significant reduction in tumor size in experimental animals. These compounds are, therefore, useful in the treatment of a wide range of disorders in mammals, including, but not limited to hyperproliferative diseases, such as head and neck cancer, including gliomas, melanoma, pancreatic carcinoma, prostate carcinoma, drug resistant lung cancer, estrogen dependent or non-dependent cancers in humans, non-small cell lung cancer and colon cancer. Non-limiting examples of estrogen dependent cancers are breast cancer and ovarian cancer. As a result of their inhibition of LTB4 activities, these compounds are useful in treating inflammatory diseases such as allergy, asthma and arthritis, and as a result of their AKT inhibition and cytokine activation, these compounds are also useful in treating viral and bacterial infections. There is currently great interest in finding new therapies for the foregoing diseases.
Salts of substituted isothiourea compounds are referred to in Miller et al., JACS, Vol. 62, 2099-2103 (1940); Shapiro, et al., Radiation Research, Vol. 7, No. 1, 22-34 (1957); King et al., Biochemistry, Vol. 17, No. 8, 1499-1506 (1978); Bauer and Welsh, J. Org. Chem. Vol. 26, No. 5, 1443-1445 (1961); Southan, et al., Br. J. Pharmacol., Vol. 114, 510-516 (1995); and Gerber, et al., Organic Synthesis, Vol. 77, 186 (2000).